The present invention relates to neuropeptide Y Y5 receptor antagonists useful in the treatment of obesity and eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that is widely distributed in the central and peripheral nervous systems. NPY is a member of the pancreatic polypeptide family that also includes peptide YY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev. Toxicol., 32, 309, 1993). NPY elicits its physiological effects by activation of at least six receptor subtypes designated Y1, Y2, Y3, Y4, Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998; Michel, M. et al., Pharmacol. Rev., 50,143,1998). Central administration of NPY to animals causes dramatically increased food intake and decreased energy expenditure (Stanley, B. and Leibowitz, S., Proc. Natl. Acad. Sci. USA 82: 3940, 1985; Billington et al., Am J. Physiol., 260, R321, 1991). These effects are believed to be mediated at least in part by activation of the NPY Y5 receptor subtype. The isolation and characterization of the NPY Y5 receptor subtype has been reported (Gerald, C. et al., Nature, 1996, 382, 168; Gerald, C. et al. WO 96/16542). Additionally, it has been reported that activation of the NPY Y5 receptor by administration of the Y5-selective agonist [D-Trp32]NPY to rats stimulates feeding and decreases energy expenditure (Gerald, C. et al., Nature, 1996, 382,168; Hwa, J. et al., Am. J. Physiol., 217 (46), R1428, 1999). Hence, compounds that block binding of NPY to the NPY Y5 receptor subtype should have utility in the treatment of obesity, disorders such as, bulimia nervosa, anorexia nervosa, and in the treatment of disorders associated with obesity such as type 11 diabetes, insulin resistance, hyperlipidemia, and hypertension.
PCT patent application WO 00/27845 describes a class of compounds, characterized therein as spiro-indolines, said to be selective neuropeptide Y Y5 receptor antagonists and useful for the treatment of obesity and the complications associated therewith. Urea derivatives indicated as possessing therapeutic activity are described in U.S. Pat. No. 4,623,662 (antiatherosclerotic agents) and U.S. Pat. No. 4,405,644 (treatment of lipometabolism).
Provisional application, U.S. Serial No. 60/232,255 describes a class of substituted urea neuropeptide Y Y5 receptor antagonists.
In one embodiment, this invention provides novel urea compounds having NPY Y5 receptor antagonist activity. In an embodiment of the invention is a compound represented by the structural formula 
or a pharmaceutically acceptable salt or solvent thereof, wherein:
X is independently N or C;
z is independently NR8 or CR3R9;
D is independently H, xe2x80x94OH, -alkyl or substituted -alkyl with the proviso that when X is N, D and the Xxe2x80x94D bond are absent;
E is independently H, -alkyl or substituted -alkyl or D and E can independently be joined together via a xe2x80x94(CH2)pxe2x80x94 bridge;
Q is independently H, -alkyl or substituted -alkyl, or D, X, Q and the carbon to which Q is shown attached can jointly form a 3 to 7-membered ring;
g, j, k, m and n can be the same or different and are independently selected;
g is 0 to 3 and when g is 0, the carbons to which (CH2)g is shown connected are no more linked;
j and k are independently 0 to 3 such that the sum of j and k is 0, 1, 2 or 3;
m and n are independently 0 to 3 such that the sum of m and n is 1, 2,3, 4 or 5;
p is 1 to 3;
R1 is 1 to 5 substituents which can be the same or different, each R1 being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, xe2x80x94NR5R6, xe2x80x94NO2, xe2x80x94CONR5R6, xe2x80x94NR5COR6, xe2x80x94NR5CONR5R6 where the two R5 moieties can be the same or different, xe2x80x94NR6C(O)OR7, xe2x80x94C(O)OR6, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94SO2NR5R6, aryl and heteroaryl;
R2 is 1 to 6 substituents which can be the same or different, each R2 being independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with the proviso that when X is N and R2 is hydroxy or alkoxy, R2 is not directly attached to a carbon adjacent to X;
R3 is independently hydrogen, -alkyl or substituted -alkyl;
R4 is 1 to 6 substituents which can be the same or different, each R4 being independently selected from hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with the proviso that when Z is NR8 and R4 is hydroxy or alkoxy, R4 is not directly attached to a carbon adjacent to the NR8;
R5 and R6 are independently hydrogen, -alkyl, substituted -alkyl or -cycloalkyl;
R7 is independently -alkyl, substituted -alkyl or -cycloalkyl;
R8 is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, xe2x80x94SO2R5O, xe2x80x94SO2NR5R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR5R11 and xe2x80x94C(O)OR10;
R9 is independently hydrogen, -alkyl, substituted -alkyl, hydroxy, alkoxy, xe2x80x94NR5R11, aryl, or heteroaryl; or R3 and R9 can be joined together and with the carbon to which they are attached form a carbocyclic or heterocyclic ring having 3 to 7 ring atoms;
R10 is -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl; aryl or heteroaryl; and
R11 is independently hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, aryl or heteroaryl.
The above statement xe2x80x9cwhen g is 0, the carbons to which (CH2)g is shown connected are no more linkedxe2x80x9d means that when g is 0, then the structural component: 
shown in formula I above becomes: 
Ureas of formula I or formula III are highly selective, high affinity NPY Y5 receptor antagonists useful for the treatment of obesity.
This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia. In one aspect, this invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I or formula III thereof, or a pharmaceutically acceptable salt or solvate of said compound, and a pharmaceutically acceptable carrier.
The present invention relates to compounds that are represented by structural formula I or formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above. The compounds of formula I or formula III can be administered as racemic mixtures or enantiomerically pure compounds.
In a preferred embodiment of the invention is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 is 1 to 5 substituents which can be the same or different, each R1 being independently selected from the group consisting of Cl, Br, I or F;
X is N;
D is absent and the Xxe2x80x94D bond is absent;
E is H;
g is 0;
j is 1;
k is 1;
m is 2;
n is 2;
R2 is H;
R3 is methyl;
R4 is H; and
Z is NR8, where R8 is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, xe2x80x94SO2R10, xe2x80x94SO2NR5R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR5R11 and xe2x80x94C(O)OR10.
A preferred embodiment of the present invention is a compound of formula II or a pharmaceutically acceptable salt or solvate thereof, wherein: 
wherein R8 is defined as herein in the Detailed Description in Table 1.
An additional preferred embodiment of the present invention is a compound of formula III or a pharmaceutically acceptable salt or solvate thereof, wherein: 
wherein
R1 is 1 to 5 substituents which can be the same or different, each R1 being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, xe2x80x94NR5R6, xe2x80x94NO2, xe2x80x94CONR5R6, xe2x80x94NR5COR6, xe2x80x94NR5CONR5R6 where the two R5 moieties can be the same or different, xe2x80x94NR6C(O)OR7, xe2x80x94C(O)OR6, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94SO2NR5R6, aryl and heteroaryl;
R3 is independently hydrogen or -alkyl; and
R8 is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, xe2x80x94SO2R10, xe2x80x94SO2NR5R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR5R11 and xe2x80x94C(O)OR10.
A further preferred group of compounds are compounds of formula III selected from the group consisting of 
or a pharmaceutically acceptable salt or solvate of said compound.
An additional preferred embodiment of the present invention is a compound of formula IV, wherein 
or a pharmaceutically acceptable salt or solvate there of, wherein
R1 is 1 to 5 substituents which can be the same or different, each R1 being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, xe2x80x94NR5R6, xe2x80x94NO2, xe2x80x94CONR5R6, xe2x80x94NR5COR6, xe2x80x94NR5CONR5R6 where the two R5 moieties can be the same or different, xe2x80x94NR6C(O)OR7, xe2x80x94C(O)OR6, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94SO2NR5R6, aryl and heteroaryl;
R3 is independently hydrogen or -alkyl; and
R8 is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, xe2x80x94SO2R10, xe2x80x94SO2NR5R11, xe2x80x94C(O)R11, xe2x80x94C(O)NR5R11 and xe2x80x94C(O)OR10.
A set of preferred compounds are listed below in the Detailed Description in Tables 2 and 3, among other preferred compounds.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as to the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d etc.
As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cMammalxe2x80x9d means humans and other animals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means an alkyl group having about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkylxe2x80x9d means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, -alkyl, aryl, -cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, carboxy and xe2x80x94C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group comprising at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means an alkenyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkenylxe2x80x9d means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, -cycloalkyl, cyano, and alkoxy. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group comprising at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. xe2x80x9cLower alkynylxe2x80x9d means an alkynyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl and 2-butynyl. The term xe2x80x9csubstituted alkynylxe2x80x9d means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and -cycloalkyl.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be unsubstituted or substituted on the ring with one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, xe2x80x94OCF3, xe2x80x94OCOalkyl, xe2x80x94OCOaryl, xe2x80x94CF3, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl and heterocyclyl. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. The xe2x80x9carylxe2x80x9d group can also be substituted by linking two adjacent carbons on its aromatic ring via a combination of one or more carbon atoms and one or more oxygen atoms such as, for example, methylenedioxy, ethylenedioxy, and the like.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl, cycloalkenyl and heterocyclyl. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, and the like.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and a naphthlenylmethyl. The bond to the parent moiety is through the alkyl.
xe2x80x9cAlkylarylxe2x80x9d means an alkyl-aryl-group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl groups is tolyl. The bond to the parent moiety is through the aryl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
xe2x80x9cHaloalkylxe2x80x9d means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, pyranyl, tetrahydrothiophenyl, morpholinyl and the like.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
xe2x80x9cHeteroaralkenylxe2x80x9d means an heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through the alkenyl.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94C(O)xe2x80x94, alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, Alkynyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, cycloalkenyl-C(O)xe2x80x94, or cycloalkynyl-C(O)xe2x80x94 group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, and cyclohexanoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-C(O)xe2x80x94 group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group is linked to an adjacent moiety through the ether oxygen.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkoxy group defined earlier linked to an adjacent moiety through a carbonyl. Non-limiting examples of alkoxycarbonyl groups include xe2x80x94C(O)xe2x80x94CH3, xe2x80x94C(O)xe2x80x94CH2CH3 and the like.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94C(O)xe2x80x94 group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94C(O)xe2x80x94 group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-S(O2)xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-S(O)xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-S(O2)xe2x80x94 group. The bond to the parent moiety is through the sulfonyl.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-S(O)xe2x80x94 group. The bond to the parent moiety is through the sulfinyl.
The term xe2x80x9coptionally substitutedxe2x80x9d means optional substitution with the specified groups, radicals or moieties.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Solvates of the compounds of the invention are also contemplated herein.
xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein the solvent molecule is H2O.
xe2x80x9cEffective amountxe2x80x9d or xe2x80x9ctherapeutically effective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective to treat a mammal (e.g., human) having a disease or condition mediated by Y Y5, and thus producing the desired therapeutic effect.
The compounds of formula I or formula III form salts which are also within the scope of this invention. Reference to a compound of formula I or formula III, herein is understood to include reference to salts thereof, unless otherwise indicated. The term xe2x80x9csalt(s)xe2x80x9d, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I or formula III contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed and are included within the term xe2x80x9csalt(s)xe2x80x9d. as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compound of formula I or formula III may be formed, for example, by reacting a compound of formula I or formula III with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1)1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food and Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of formula I or formula III, and salts and solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts and solvates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms xe2x80x9csaltxe2x80x9d, xe2x80x9csolvatexe2x80x9d and the like, is intended to equally apply to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers, or racemates of the inventive compounds.
When any variable (e.g., aryl, heterocycle, R1, etc.) occurs more than one time in any constituent or in formula I or formula III, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible. only if such combinations result in stable compounds.
For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and l isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I or formula III.
Compounds of formula I or formula III can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I or formula III may form pharmaceutically acceptable salts with organic and inorganic acids. For example, pyrido-nitrogen atoms may form salts with strong acids, while tertiary amino groups may form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
A further group of preferred compounds are those listed below in Table 2.
as well as their pharmaceutically acceptable salts or solvates.
An even further preferred group of compounds are those listed below in Table 3.
as well as their pharmaceutically acceptable salts or solvates.
An even further preferred group of compounds are compounds from the group consisting of: 
as well as their pharmaceutically acceptable salts or solvates.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by the neuropeptide Y Y5 receptor by administering a therapeutically effective amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound to the mammal.
A dosage for the invention is about 0.001 to 30 mg/kg/day of the formula I or formula III compound. An additional dosage range is about 0.001 to 3 mg/kg/day of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method of treating obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I or formula III or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating metabolic and eating disorders such as bulimia and anorexia comprising administering to a mammal a therapeutically effective amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a mammal a therapeutically effective amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a mammal a therapeutically effective amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating Type II diabetes comprising administering to a mammal a therapeutically effective amount of a compound of formula I or formula III or a pharmaceutically acceptable salt of said compound.
In addition to the xe2x80x9cdirectxe2x80x9d effect of the compounds of this invention on the neuropeptide Y Y5 receptor subtype, there are diseases and conditions that will benefit from the weight loss such as insulin resistance, impaired glucose tolerance, Type II Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers, and sleep apnea.
This invention is also directed to pharmaceutical compositions, which comprise an amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound or of said and a pharmaceutically acceptable carrier therefor.
Compounds of formula I or formula III can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below.
Compounds of formula I where X is N, D is absent, A is absent, E is H, R2 is H, R4 is H, j is 1, k is 1, m is 2, n is 2, and Z is NR8 can be prepared by Scheme 1, as follows: 
Compounds of formula I wherein X is C, D is H, A is absent, E is H, R2 is H, R4 is H, j is 1, k is 1, m is 2, n is 2 and Z is NR8 can be prepared by Scheme 4, as follows: 
Combinatorial libraries of compounds of formula I can also be prepared using solid phase chemistry as shown in the schemes above.
Alternative mechanistic pathways and analogous structures within the scope of the invention would be apparent to those skilled in the art.
Starting materials are prepared by known methods and/or methods described in the Preparations.
The compounds of formula I or formula III exhibit Y Y5 receptor antagonizing activity, which has been correlated with pharmaceutical activity for treating metabolic disorders, such as obesity, eating disorders such as hyperphagia, and diabetes.
The compounds of formula I or formula III display pharmacological activity in a test procedure designed to demonstrate Y Y5 receptor antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses.
cAMP Assay
HEK-293 cells expressing the Y5 receptor subtype were maintained in Dulbecco""s modified Eagles"" media (Gico-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin and 200 xcexcg/mi Geneticin(copyright)(GibcoBRL #11811-031) under a humidified 5% CO2 atmosphere. Two days prior to assay, cells were released from T-175 tissue culture flasks using cell dissociation solution (1xc3x97; non-enzymatic [Sigma #C-5914]) and seeded into 96-well, flat-bottom tissue culture plates at a density of 15,000 to 20,000 cells per well. After approximately 48 hours, the cell monolayers were rinsed with Hank""s balanced salt solution (HBSS) then pre-incubated with approximately 150 xcexcl/well of assay buffer (HBSS supplemented with 4 mM MgCl2, 10 mM HEPES, 0.2% BSA [HH]) containing 1 mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #1-587) with or without the antagonist compound of interest at 37xc2x0 C. After 20 minutes the 1 mM IBMX-HH assay buffer (xc2x1antagonist compound) was removed and replaced with assay buffer containing 1.5 xcexcM (CHO cells) or 5 xcexcM (HEK-293 cells) forskolin (Sigma #F-6886) and various concentrations of NPY in the presence or absence of one concentration of the antagonist compound of interest. At the end of 10 minutes, the media were removed and the cell monolayers treated with 75 xcexcl ethanol. The tissue culture plates were agitated on a platform shaker for 15 minutes, after which the plates were transferred to a warm bath in order to evaporate the ethanol. Upon bringing all wells to dryness, the cell residues were re-solubilized with 250 xcexcl FlashPlate(copyright) assay buffer. The amount of cAMP in each well was quantified using the [125I]-cAMP FlashPlate(copyright) kit (NEN #SMP-001) and according to the protocol provided by the manufacturer. Data were expressed as either pmol cAMP/ml or as percent of control. All data points were determined in triplicate and EC50""s (nM) were calculated using a nonlinear (sigmoidal) regression equation (GraphPad Prism(trademark)). The KB of the antagonist compound was estimated using the following formula:
KB=[B]/(1xe2x88x92{[Axe2x80x2]/[A]})
where
[A] is the EC50 of the agonist (NPY) in the absence of antagonist,
[Axe2x80x2] is the EC50 of the agonist (NPY) in the presence of antagonist, and
[B] is the concentration of the antagonist.
NPY Receptor Binding Assay
Human NPY Y5 receptors were expressed in CHO cells. Binding assays were performed in 50 mM HEPES, pH 7.2, 2.5 mM CaCl2, 1 mM MgCl2 and 0.1% BSA containing 5-10 xcexcg of membrane protein and 0.1 nM 125L-peptide YY in a total volume of 200 xcexcl. Non-specific binding was determined in the presence of 1 xcexcM NPY. The reaction mixtures were incubated for 90 minutes at room temperature then filtered through Millipore MAFC glass fiber filter plates which had been pre-soaked in 0.5% polyethleneimine. The filters were washed with phosphate-buffered saline, and radioactivity was measured in a Packard TopCount scintillation counter.
For the compounds of this invention, a range of NPY Y5 receptor binding activity (Ki values) of from about 0.2 nM to about 2,000 nM was observed. Compounds of this invention preferably have a binding activity in the range of from about 0.2 nM to about 1,000 nM, more preferably from about 0.2 to about 100 nM, and most preferably from about 0.2 to about 10 nM.
Yet another aspect of this invention are combinations of a compound of formula I or formula III, or a pharmaceutically acceptable salt of said compound and other compounds as described below.
One such aspect of this invention is a method for treating obesity comprising administering to a mammal (e.g., a female or male human)
a. an amount of a first compound, said first compound being a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound; and
b. an amount of a second compound, said second compound being an anti-obesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist wherein the amounts of the first and second compounds result in a therapeutic effect.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising
a first compound, said first compound being a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound
a second compound, said second compound being an anti-obesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic, or an NPY antagonist; and/or optionally a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention is a kit comprising:
a. an amount of a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. an amount of an anti-obesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
Preferred anti-obesity and/or anorectic agents (taken singly or in any combination thereof) in the above combination methods, combination compositions and combination kits are:
phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as xe2x80x9cleptinxe2x80x9d), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.
Another aspect of this invention is a method treating diabetes comprising administering to a mammal (e.g., a female or male human)
a. an amount of a first compound, said first compound being a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound; and
b. an amount of a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising
a first compound, said first compound being a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound;
a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention is a kit comprising:
a. an amount of a formula I or formula III compound, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. an amount of an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.